Complemen Assembly of C3 convertase and serotonin act on smooth muscle to cause contraction or on small blood vessels to increase vascular permeability. groupof C Bindingtoeceptorsonneutophihtirmhtsadcafd at the surface of the activator.Bound C4b then binds C2n s.hou f whiche mos mation.Control of anaphylatoxin activity is achieved catalytic pathway C3 convertase,with a serine active site in C2a and Kinin-like activity of C2b exhibiting specific proteolytic activity towards C3.This The c2b fragme t itself or a smaller proteolvtic fr Ck(b00 Da)from the C-terminal end of Incidentally,native C3b.like C4b,is able to bind covalently to the activator surface in the vicinity of the troke in convertase as wel tothe C3b moiety of the C3 contrast with Ca and Ca activities.C2k is not inhibited ).the clas CPro by antihistaminic drugs. which C2a acquires specificity for the cleavage of C5. Biological activities of C3b and C4b Opsonization and endocytosis Biological effects of the pathway(Table 3) Native C4b and C3b are able to bind covalently to nucleophilic groups on any antigen or pathogen.The Anaphylatoxins C3a and C4a C4a and C3a are 77amino acid polypeptides released from thechains of C4and C3 respectively upon proteolysis by MBL/MASP complex (C4)and C3 convertase Binding and cellular uptake are mediated by complement receptor CR1.The binding of C4b or C3b to CRI is amines from intracellular granules.Released histamine by factor capacity to bind with high efficiency to complement complement pathway eceptor CR3 appears.Subsequent proteolysis of ic3b C2b and C2k C able tobind c appearsfrom muscles human body against foreign pathogens C3a.C4a Vascula Cont Clearance of immune complexes muscles covalently to the immune C3b(C4b) Immune adherence and way.C3b and C4b-associated immune complexes are complexes Antigen localization in ne re Kuper cels,and their uptake by these cel Antigen presentation Roles in the immune response C3b-or C4b-associated antigens are more efficiently iC3b presented by antigen-pres nting cells to cas of C3b C4b-bound antigens has been observed.Also.signalling by 6 ublishing Group/www.els.netAssembly of C3 convertase When activated C1 cleaves C4, the resulting C4b fragment is able to bind covalently to –NH2 or –OH groups on proteins or polysaccharides in the immediate vicinity of C1 at the surface of the activator. Bound C4b then binds C2 in the presence of magnesium, which renders this protein available for limited proteolysis by C1. The catalytic fragment C2a remains bound to C4b, resulting in the formation of a bimolecular complex C4bC2a, the classical pathway C3 convertase, with a serine active site in C2a and exhibiting specific proteolytic activity towards C3. This complex protease is central to the complement system as it generates fragments C3a and C3b, both responsible for major biological activities. Incidentally, native C3b, like C4b, is able to bind covalently to the activator surface in the vicinity of the convertase, as well as to the C3b moiety of the C3 convertase itself, leading to a three-protein complex (C4bC2aC3b), the classical pathway C5 convertase, in which C2a acquires specificity for the cleavage of C5. Biological effects of the pathway (Table 3) Anaphylatoxins C3a and C4a C4a and C3a are 77 amino acid polypeptides released from the a chains of C4 and C3 respectively upon proteolysis by C1 or the MBL/MASP complex (C4) and C3 convertase (C3). Binding of these peptides to receptors on the surface of mast cells and basophils initiates a release of vasoactive amines from intracellular granules. Released histamine and serotonin act on smooth muscle to cause contraction or on small blood vessels to increase vascular permeability. Binding to receptors on neutrophils stimulates a release of lysosomal enzymes. C3a is by far the most efficient of the two anaphylatoxins, both of which contribute to inflam￾mation. Control of anaphylatoxin activity is achieved efficiently in vivo by a plasma carboxypeptidase N (anaphylatoxin inactivator) which removes the C-terminal arginine residue from each peptide. Kinin-like activity of C2b The C2b fragment itself or a smaller proteolytic fragment C2k (about 1500 Da) from the C-terminal end of C2b has been implicated as the causative factor for hereditary angioedema. Uncontrolled activity of C1 towards C4bC2 leads to overproduction of C2k and angioedema stroke. In contrast with C3a and C4a activities, C2k is not inhibited by antihistaminic drugs. Biological activities of C3b and C4b Opsonization and endocytosis Native C4b and C3b are able to bind covalently to nucleophilic groups on any antigen or pathogen. The bound fragments then bind noncovalently to membrane receptors on many phagocytes, leading to endocytosis of soluble antigens or to phagocytosis of diverse pathogens. Binding and cellular uptake are mediated by complement receptor CR1. The binding of C4b or C3b to CR1 is transient, due to proteolysis of these fragments by factor I into C4c and C4d and into iC3b and C3f, respectively. In the case of iC3b the affinity for CR1 is decreased, whereas a capacity to bind with high efficiency to complement receptor CR3 appears. Subsequent proteolysis of iC3b leads to fragment C3dg, able to bind complement receptor CR2. Receptor CR3 appears from the life length of iC3b as the most efficient in phagocytosis. This activity of C3 and C4 fragments is one of the first defence mechanisms of the human body against foreign pathogens. Clearance of immune complexes C3b and C4b are able to bind covalently to immune complexes which activate the classical complement path￾way. C3b- and C4b-associated immune complexes are loaded on erythrocytes through CR1 receptors and transported to the liver where proteolysis of C3b or C4b leads to the release of the complexes from the erythrocytes, with subsequent binding of the immune complexes to Fc receptors of Kupffer cells, and their uptake by these cells. Roles in the immune response C3b- or C4b-associated antigens are more efficiently processed and presented by antigen-presenting cells to T lymphocytes than antigens alone. In the case of presenting B lymphocytes, improved uptake and processing of C3b/ C4b-bound antigens has been observed. Also, signalling by Table 3 Biological activities of components of the classical complement pathway C2b and C2k Vascular permeability and contraction of smooth muscles C3a, C4a Vascular permeability Contraction of smooth muscles C3b (C4b) Immune adherence and opsonization Elimination of immune complexes Antigen localization in lymphoid tissues Phagocytosis of immune complexes Antigen presentation iC3b Phagocytosis Antibody-dependent cytotoxicity Complement: Classical Pathway 6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net